Although cancer of the colon is often a curable disease when localized to the bowel, recurrence following surgery is a major problem, and often is the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement, i.e. the presence of metastases. Metastasis of colorectal cancer is a serious clinical problem and the prognosis of current clinical treatment is poor. Colon cancer metastases are very common in liver, and liver is the site for adenoviruses accumulation after administration.
There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, and ulcerative colitis. More common conditions with an increased risk include: a personal history of colorectal cancer or adenomas, first degree family history of colorectal cancer or adenomas, and a personal history of ovarian, endometrial, or breast cancer.
PRL-3 protein tyrosine phosphatase gene has been recently found to be specifically expressed at a high level in metastatic colon cancers (Saha et al. (2001) Science 294:1343). Originally identified as a member of a group of up-regulated genes in a metastatic colon cancer library, identified by the serial analysis of gene expression (SAGE), the PRL-3 gene was confirmed to be elevated in only the metastases, not the primary cancer or pre-malignant adenomas.
PRL-3 is a small tyrosine phosphatase. In normal human tissues, it is expressed predominantly in muscle and heart by Northern blot (Matter et al. (2001) Biochem Biophys Res Commun. 283(5):1061-8). It can not be detected from Hela or A431 (epidermal carcinoma cell) cells, and in the mouse can only be detected weakly in some regions of intestine (Zeng et al. (2000) J Biol Chem. 275(28):21444-52). The Volgestein group's study also indicated that in various stages of colorectal cancer, PRL-3 was expressed at low levels in normal colorectal epithelium and benign tumors. However, PRL-3 was expressed at relatively high levels in each of 12 colorectal cancer metastases detected. From the samples collected at different places of same patients, only the metastatic lesions had significant PRL-3 expression, whereas samples from normal colorectal epithelium or primary tumors had little or no expression.
Several viruses have recently come forth as both vehicles for gene therapy and as candidate anticancer agents. Among them adenovirus, a mildly pathogenic human virus that propagates prolifically in epithelial cells, the origin of many human cancers. Adenovirus has emerged as a virus that can be engineered with oncotropic properties. See, for example, U.S. Pat. No. 5,846,945 (Onyx); U.S. Pat. No. 5,801,029 (Onyx); U.S. Pat. No. 5,747,469 (Univ Texas); PCTUS1999/08592 (WO 99/59604; Onyx) or PCT/US1998/03514 (WO 98/35554; Canji); PCT/US1997/22036 (WO 98/29555; Onyx). Replication competent adenovirus vectors have been designed to selectively replicate in tumor cells. Improving the delivery of these adenoviruses, both to local-regional and disseminated disease, as well as improving the virus to promote intratumoral spread are of particular interest.
Several experimental cancer therapies utilize various aspects of adenovirus or adenovirus vectors. See, for example, U.S. Pat. No. 5,846,945; U.S. Pat. No. 5,801,029; PCT/US99/08592; U.S. Pat. No. 5,747,469; PCT/US98/03514; and PCT/US97/22036.
Although replication competent adenoviruses may be able to achieve selective targeting and amplification for the treatment of local and disseminated cancer, there remains a need for improvement in both the adenovirus vectors themselves and methods for their use. Preliminary results suggest that the features of effective treatment strategies for various types of cancer may require development of specific adenovirus vectors and/or methods particular to the type of cancer under treatment. Although chemotherapy and immunotherapy are the most prevalent current therapeutic strategies for disseminated tumors, both toxic side effects and lack of efficacy remain a problem.
There is, therefore, substantial interest in development of viral vectors which enable the targeting of specific cancers in vivo.